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Special Issue "Rare Kidney Diseases: New Translational Research Approach to Improve Diagnosis and Therapy"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 30 April 2020.

Special Issue Editors

Dr. Gianluigi Zaza
E-Mail Website
Guest Editor
Renal Unit, Department of Medicine, University of Verona, Italy
Interests: recognition of biological elements regulating acute and chronic renal disorders; identification of new diagnostic biomarkers for glomerular diseases, tubule-interstitial renal diseases; selection of novel therapeutic targets for rare and complex kidney disorders; pharmacogenomics/genetics
Prof. Giovanni Gambaro
E-Mail
Guest Editor
Renal Unit, Department of Medicine, University of Verona, Italy
Interests: rare kidney diseases; kidney cystic disorders; nephrolithiasis; genetic/genomic and biomolecular determinants of rare and complex renal diseases; chronic kidney disease

Special Issue Information

Dear Colleagues,

Rare kidney diseases comprise a group of 150 different life-threatening or chronically debilitating disorders (e.g., Fabry Disease, autosomal recessive polycystic disease, medullary cystic disease, Alport Syndrome, primary hyperoxaluria, primary glomerulonephritis, systemic vasculitis, and familial/recurrent hemolytic uremic syndrome) that affect very small numbers of people (<1 in 2000 individuals in Europe and <200,000 in USA) with local or systemic manifestations. For several years, research and development of treatments in this field have been neglected in favor of more common diseases. The main reasons of the lack of interest in rare kidney diseases seem to be the small numbers of patients and limited epidemiological data on the natural history of many of these diseases.

Rare diseases can affect people differently. Even patients with the same condition can exhibit very different signs and symptoms, or there may be many subtypes of the same condition. This diversity constitutes a significant challenge to healthcare practitioners and scientists alike in terms of being able to acquire sufficient experience for the most appropriate and timely definition, diagnosis, and management.

Fortunately, in the last ten years, concerted efforts have led to a marked improvement in the understanding of these disorders. In particular, an important step forward has been taken with the employment of innovative technologies (including next-generation sequencing) in order to replace obsolete phenotypic classifications and to discover new useful diagnostic biomarkers. These new tools are in fact becoming part of routine clinical practice, increasing diagnostic accuracy and facilitating genetic counseling.

Moreover, biomedical research, providing insights into the pathologies of these rare diseases and elucidating their underlying mechanisms, is revealing new therapeutic avenues and driving the industry to develop safer and more effective orphan drugs.

Finally, in this field, it is desirable that in future, the cross-talk between basic scientists and clinicians could achieve a great clinical benefit also by improving the quality of life of these patients.

This Special Issue welcomes scientific contributions and critical reviews describing new pathogenetic insights, reporting novel and specific disease biomarkers and underlying new pharmacological targets or therapies for rare diseases of the kidney and urinary tract.

Prof. Gianluigi Zaza
Prof. Giovanni Gambaro
Guest Editor

Manuscript Submission Information

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Keywords

  • Rare kidney diseases
  • new diagnostic biomarkers
  • selection of novel therapeutic targets for rare and complex kidney disorders
  • pharmacogenomics/genetics

Published Papers (8 papers)

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Research

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Open AccessArticle
Genetic Analyses in Dent Disease and Characterization of CLCN5 Mutations in Kidney Biopsies
Int. J. Mol. Sci. 2020, 21(2), 516; https://doi.org/10.3390/ijms21020516 - 14 Jan 2020
Abstract
Dent disease (DD), an X-linked renal tubulopathy, is mainly caused by loss-of-function mutations in CLCN5 (DD1) and OCRL genes. CLCN5 encodes the ClC-5 antiporter that in proximal tubules (PT) participates in the receptor-mediated endocytosis of low molecular weight proteins. Few studies have analyzed [...] Read more.
Dent disease (DD), an X-linked renal tubulopathy, is mainly caused by loss-of-function mutations in CLCN5 (DD1) and OCRL genes. CLCN5 encodes the ClC-5 antiporter that in proximal tubules (PT) participates in the receptor-mediated endocytosis of low molecular weight proteins. Few studies have analyzed the PT expression of ClC-5 and of megalin and cubilin receptors in DD1 kidney biopsies. About 25% of DD cases lack mutations in either CLCN5 or OCRL genes (DD3), and no other disease genes have been discovered so far. Sanger sequencing was used for CLCN5 gene analysis in 158 unrelated males clinically suspected of having DD. The tubular expression of ClC-5, megalin, and cubilin was assessed by immunolabeling in 10 DD1 kidney biopsies. Whole exome sequencing (WES) was performed in eight DD3 patients. Twenty-three novel CLCN5 mutations were identified. ClC-5, megalin, and cubilin were significantly lower in DD1 than in control biopsies. The tubular expression of ClC-5 when detected was irrespective of the type of mutation. In four DD3 patients, WES revealed 12 potentially pathogenic variants in three novel genes (SLC17A1, SLC9A3, and PDZK1), and in three genes known to be associated with monogenic forms of renal proximal tubulopathies (SLC3A, LRP2, and CUBN). The supposed third Dent disease-causing gene was not discovered. Full article
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Open AccessArticle
Mitochondrial Dynamics of Proximal Tubular Epithelial Cells in Nephropathic Cystinosis
Int. J. Mol. Sci. 2020, 21(1), 192; https://doi.org/10.3390/ijms21010192 - 26 Dec 2019
Abstract
Nephropathic cystinosis is a rare lysosomal storage disorder caused by mutations in CTNS gene leading to Fanconi syndrome. Independent studies reported defective clearance of damaged mitochondria and mitochondrial fragmentation in cystinosis. Proteins involved in the mitochondrial dynamics and the mitochondrial ultrastructure were analyzed [...] Read more.
Nephropathic cystinosis is a rare lysosomal storage disorder caused by mutations in CTNS gene leading to Fanconi syndrome. Independent studies reported defective clearance of damaged mitochondria and mitochondrial fragmentation in cystinosis. Proteins involved in the mitochondrial dynamics and the mitochondrial ultrastructure were analyzed in CTNS−/− cells treated with cysteamine, the only drug currently used in the therapy for cystinosis but ineffective to treat Fanconi syndrome. CTNS−/− cells showed an overexpression of parkin associated with deregulation of ubiquitination of mitofusin 2 and fission 1 proteins, an altered proteolytic processing of optic atrophy 1 (OPA1), and a decreased OPA1 oligomerization. According to molecular findings, the analysis of electron microscopy images showed a decrease of mitochondrial cristae number and an increase of cristae lumen and cristae junction width. Cysteamine treatment restored the fission 1 ubiquitination, the mitochondrial size, number and lumen of cristae, but had no effect on cristae junction width, making CTNS−/− tubular cells more susceptible to apoptotic stimuli. Full article
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Open AccessArticle
Proteomic Analysis of Urinary Extracellular Vesicles Reveals a Role for the Complement System in Medullary Sponge Kidney Disease
Int. J. Mol. Sci. 2019, 20(21), 5517; https://doi.org/10.3390/ijms20215517 - 05 Nov 2019
Abstract
Medullary sponge kidney (MSK) disease is a rare and neglected kidney condition often associated with nephrocalcinosis/nephrolithiasis and cystic anomalies in the precalyceal ducts. Little is known about the pathogenesis of this disease, so we addressed the knowledge gap using a proteomics approach. The [...] Read more.
Medullary sponge kidney (MSK) disease is a rare and neglected kidney condition often associated with nephrocalcinosis/nephrolithiasis and cystic anomalies in the precalyceal ducts. Little is known about the pathogenesis of this disease, so we addressed the knowledge gap using a proteomics approach. The protein content of microvesicles/exosomes isolated from urine of 15 MSK and 15 idiopathic calcium nephrolithiasis (ICN) patients was investigated by mass spectrometry, followed by weighted gene co-expression network analysis, support vector machine (SVM) learning, and partial least squares discriminant analysis (PLS-DA) to select the most discriminative proteins. Proteomic data were verified by ELISA. We identified 2998 proteins in total, 1764 (58.9%) of which were present in both vesicle types in both diseases. Among the MSK samples, only 65 (2.2%) and 137 (4.6%) proteins were exclusively found in the microvesicles and exosomes, respectively. Similarly, among the ICN samples, only 75 (2.5%) and 94 (3.1%) proteins were exclusively found in the microvesicles and exosomes, respectively. SVM learning and PLS-DA revealed a core panel of 20 proteins that distinguished extracellular vesicles representing each clinical condition with an accuracy of 100%. Among them, three exosome proteins involved in the lectin complement pathway maximized the discrimination between MSK and ICN: Ficolin 1, Mannan-binding lectin serine protease 2, and Complement component 4-binding protein β. ELISA confirmed the proteomic results. Our data show that the complement pathway is involved in the MSK, revealing a new range of potential therapeutic targets and early diagnostic biomarkers. Full article
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Review

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Open AccessReview
A Narrative Review on C3 Glomerulopathy: A Rare Renal Disease
Int. J. Mol. Sci. 2020, 21(2), 525; https://doi.org/10.3390/ijms21020525 - 14 Jan 2020
Abstract
In April 2012, a group of nephrologists organized a consensus conference in Cambridge (UK) on type II membranoproliferative glomerulonephritis and decided to use a new terminology, “C3 glomerulopathy” (C3 GP). Further knowledge on the complement system and on kidney biopsy contributed toward distinguishing [...] Read more.
In April 2012, a group of nephrologists organized a consensus conference in Cambridge (UK) on type II membranoproliferative glomerulonephritis and decided to use a new terminology, “C3 glomerulopathy” (C3 GP). Further knowledge on the complement system and on kidney biopsy contributed toward distinguishing this disease into three subgroups: dense deposit disease (DDD), C3 glomerulonephritis (C3 GN), and the CFHR5 nephropathy. The persistent presence of microhematuria with or without light or heavy proteinuria after an infection episode suggests the potential onset of C3 GP. These nephritides are characterized by abnormal activation of the complement alternative pathway, abnormal deposition of C3 in the glomeruli, and progression of renal damage to end-stage kidney disease. The diagnosis is based on studying the complement system, relative genetics, and kidney biopsies. The treatment gap derives from the absence of a robust understanding of their natural outcome. Therefore, a specific treatment for the different types of C3 GP has not been established. Recommendations have been obtained from case series and observational studies because no randomized clinical trials have been conducted. Current treatment is based on corticosteroids and antiproliferative drugs (cyclophosphamide, mycophenolate mofetil), monoclonal antibodies (rituximab) or complement inhibitors (eculizumab). In some cases, it is suggested to include sessions of plasma exchange. Full article
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Open AccessReview
Nephrocalcinosis: A Review of Monogenic Causes and Insights They Provide into This Heterogeneous Condition
Int. J. Mol. Sci. 2020, 21(1), 369; https://doi.org/10.3390/ijms21010369 - 06 Jan 2020
Abstract
The abnormal deposition of calcium within renal parenchyma, termed nephrocalcinosis, frequently occurs as a result of impaired renal calcium handling. It is closely associated with renal stone formation (nephrolithiasis) as elevated urinary calcium levels (hypercalciuria) are a key common pathological feature underlying these [...] Read more.
The abnormal deposition of calcium within renal parenchyma, termed nephrocalcinosis, frequently occurs as a result of impaired renal calcium handling. It is closely associated with renal stone formation (nephrolithiasis) as elevated urinary calcium levels (hypercalciuria) are a key common pathological feature underlying these clinical presentations. Although monogenic causes of nephrocalcinosis and nephrolithiasis are rare, they account for a significant disease burden with many patients developing chronic or end-stage renal disease. Identifying underlying genetic mutations in hereditary cases of nephrocalcinosis has provided valuable insights into renal tubulopathies that include hypercalciuria within their varied phenotypes. Genotypes affecting other enzyme pathways, including vitamin D metabolism and hepatic glyoxylate metabolism, are also associated with nephrocalcinosis. As the availability of genetic testing becomes widespread, we cannot be imprecise in our approach to nephrocalcinosis. Monogenic causes of nephrocalcinosis account for a broad range of phenotypes. In cases such as Dent disease, supportive therapies are limited, and early renal replacement therapies are necessitated. In cases such as renal tubular acidosis, a good renal prognosis can be expected providing effective treatment is implemented. It is imperative we adopt a precision-medicine approach to ensure patients and their families receive prompt diagnosis, effective, tailored treatment and accurate prognostic information. Full article
Open AccessReview
A New Vision of IgA Nephropathy: The Missing Link
Int. J. Mol. Sci. 2020, 21(1), 189; https://doi.org/10.3390/ijms21010189 - 26 Dec 2019
Abstract
IgA Nephropathy (IgAN) is a primary glomerulonephritis problem worldwide that develops mainly in the 2nd and 3rd decade of life and reaches end-stage kidney disease after 20 years from the biopsy-proven diagnosis, implying a great socio-economic burden. IgAN may occur in a sporadic [...] Read more.
IgA Nephropathy (IgAN) is a primary glomerulonephritis problem worldwide that develops mainly in the 2nd and 3rd decade of life and reaches end-stage kidney disease after 20 years from the biopsy-proven diagnosis, implying a great socio-economic burden. IgAN may occur in a sporadic or familial form. Studies on familial IgAN have shown that 66% of asymptomatic relatives carry immunological defects such as high IgA serum levels, abnormal spontaneous in vitro production of IgA from peripheral blood mononuclear cells (PBMCs), high serum levels of aberrantly glycosylated IgA1, and an altered PBMC cytokine production profile. Recent findings led us to focus our attention on a new perspective to study the pathogenesis of this disease, and new studies showed the involvement of factors driven by environment, lifestyle or diet that could affect the disease. In this review, we describe the results of studies carried out in IgAN patients derived from genomic and epigenomic studies. Moreover, we discuss the role of the microbiome in the disease. Finally, we suggest a new vision to consider IgA Nephropathy as a disease that is not disconnected from the environment in which we live but influenced, in addition to the genetic background, also by other environmental and behavioral factors that could be useful for developing precision nephrology and personalized therapy. Full article
Open AccessReview
Pseudoxanthoma Elasticum, Kidney Stones and Pyrophosphate: From a Rare Disease to Urolithiasis and Vascular Calcifications
Int. J. Mol. Sci. 2019, 20(24), 6353; https://doi.org/10.3390/ijms20246353 - 17 Dec 2019
Abstract
Pseudoxanthoma elasticum is a rare disease mainly due to ABCC6 gene mutations and characterized by ectopic biomineralization and fragmentation of elastic fibers resulting in skin, cardiovascular and retinal calcifications. It has been recently described that pyrophosphate (a calcification inhibitor) deficiency could be the [...] Read more.
Pseudoxanthoma elasticum is a rare disease mainly due to ABCC6 gene mutations and characterized by ectopic biomineralization and fragmentation of elastic fibers resulting in skin, cardiovascular and retinal calcifications. It has been recently described that pyrophosphate (a calcification inhibitor) deficiency could be the main cause of ectopic calcifications in this disease and in other genetic disorders associated to mutations of ENPP1 or CD73. Patients affected by Pseudoxanthoma Elasticum seem also prone to develop kidney stones originating from papillary calcifications named Randall’s plaque, and to a lesser extent may be affected by nephrocalcinosis. In this narrative review, we summarize some recent discoveries relative to the pathophysiology of this mendelian disease responsible for both cardiovascular and renal papillary calcifications, and we discuss the potential implications of pyrophosphate deficiency as a promoter of vascular calcifications in kidney stone formers and in patients affected by chronic kidney disease. Full article
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Open AccessReview
Complement and Complement Targeting Therapies in Glomerular Diseases
Int. J. Mol. Sci. 2019, 20(24), 6336; https://doi.org/10.3390/ijms20246336 - 16 Dec 2019
Abstract
The complement cascade is part of the innate immune system whose actions protect hosts from pathogens. Recent research shows complement involvement in a wide spectrum of renal disease pathogenesis including antibody-related glomerulopathies and non-antibody-mediated kidney diseases, such as C3 glomerular disease, atypical hemolytic [...] Read more.
The complement cascade is part of the innate immune system whose actions protect hosts from pathogens. Recent research shows complement involvement in a wide spectrum of renal disease pathogenesis including antibody-related glomerulopathies and non-antibody-mediated kidney diseases, such as C3 glomerular disease, atypical hemolytic uremic syndrome, and focal segmental glomerulosclerosis. A pivotal role in renal pathogenesis makes targeting complement activation an attractive therapeutic strategy. Over the last decade, a growing number of anti-complement agents have been developed; some are approved for clinical use and many others are in the pipeline. Herein, we review the pathways of complement activation and regulation, illustrate its role instigating or amplifying glomerular injury, and discuss the most promising novel complement-targeting therapies. Full article
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Genetic analyses in Dent disease and characterization of CLCN5 mutations in kidney biopsies
Author: Franca Anglani
Abstract: Phenotypic and genetic heterogeneity characterizes Dent disease (DD), an X-linked renal tubulopathy mainly caused by loss-of-function mutations in CLCN5 (DD1) and OCRL genes. About 25% of DD cases lacks mutation in either genes (DD3) and no other disease-genes are known. CLCN5 encodes ClC-5 antiporter that participates to receptor-mediated protein endocytosis in proximal tubules (PT). Few studies have analyzed PT ClC-5 expression in DD1 patients. This paper describes 23 novel CLCN5 disease-causing mutations and shows that PT ClC-5 expression is lost in DD1 resulting in defective trafficking of megalin and cubilin. Analyzing by Whole Exome Sequencing seven DD3 patients also suggests that the concomitant presence of likely pathogenic variants in genes encoding megalin, cubilin and NHE3, components of PT endocytic apparatus, may have a role in determining DD-like phenotypes.

Title: A new vision of IgA Nephropathy: the missing link
Author: Fabio Sallustio1, 2, Claudia Curci2, Vincenzo Di Leo2, Francesco Pesce2, Loreto Gesualdo2
Affiliations: 1. Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari "Aldo Moro", Bari, Italy; 2. Nephrology, Dialysis and Transplantation Unit, DETO, University “Aldo Moro” Bari, Italy
Abstract: IgA Nephropathy (IgAN) is a primary glomerulonephritis worldwide  that develops mainly  in the 2nd and 3rd decade of life and reaches end-stage kidney disease (ESKD) after 20 years from the biopsy-proven diagnosis implying a great socio-economical burden. IgAN may occur in a sporadic or familial form, with familial clustering suggesting a strong genetic involvement. Several extended kindreds segregating IgAN have been reported in different areas of the world. The routine urine analysis carried out on first degree relatives of IgAN patients shows a 25% higher occurrence of urinary abnormalities compared to unrelated subjects and a higher risk of developing IgAN. Furthermore, studies on familial IgAN have shown that 66% of asymptomatic relatives carry immunological defects such as high IgA serum levels, abnormal spontaneous in vitro production of IgA from peripheral blood mononuclear cells (PBMCs), high serum levels of aberrantly glycosylated IgA1 and altered PBMC cytokine production profile. These familial immunological abnormalities, reported in different ethnic groups suggest, firstly that some individuals may be carriers of immunological abnormalities but continue to be apparently healthy and secondly that additional cofactors are required for the development of IgAN. These findings led to focalize the attention on new perspective to study the pathogenesis of this disease and new studies showed the involvement of factors driven by environment, lifestyle or diet that could affect the disease.
             In this review, we describe the results of studies carried out in IgAN patients moving  from genomic studies, to transcriptomics carried out on circulating immune cells and kidney biopsy specimens and then to epigenomics. Finally, we suggest a new vision to consider the IgA Nephropathy not disconnected from the environment in which we live but influenced, in addition to the genetic background, also by other environmental and behavioral factors that could be useful to develop precision nephrology and personalized therapy.

 

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